Intermediate compounds for the preparation of new quinolone-and naphthyridonecarboxylic acid derivatives

ABSTRACT

The invention relates to new intermediate compounds for preparation of new quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in the 7-position by an unsatured bicyclic amine radical, their salts, processes for their preparation and antibacterial compositions comprising these compounds.

This is a division of application Ser. No. 08/583,685, filed on Jan. 5,1996 U.S. Pat. No. 5,703,094.

The invention relates to new quinolone- and naphthyridonecarboxylic acidderivatives which are substituted in the 7-position by an unsaturatedbicyclic amine radical, their salts, processes for their preparation andantibacterial compositions comprising these compounds.

Quinolonecarboxylic acids which are substituted in the 7-position by abicyclic unsaturated amine radical are already known from the patentapplications EP 520 240 (Bayer), DE 4 230 804 (Bayer) and JP 4 253 973(Banyu). These compounds are distinguished by a high antibacterialactivity. However, they have the disadvantage that they have arelatively high genotoxic potential, which renders their use asmedicaments problematic. The invention is therefore based on the objectof discovering compounds which show a reduction in genotoxic properties,coupled with a high antibacterial activity.

It has now been found that the compounds of the formula (I)

    T-Q                                                        (I)

in which

Q denotes a radical of the formulae ##STR1## wherein R¹ represents alkylwhich has 1 to 4 carbon atoms and is optionally mono-or disubstituted byhalogen or hydroxyl, alkenyl having 2 to 4 carbon atoms, cycloalkylwhich has 3 to 6 carbon atoms and is optionally substituted by 1 or 2fluorine atoms, bicyclo 1.1.1!-pent-1-yl, 1,1-dimethylpropargyl,3-oxetanyl, methoxy, amino, methylamino, dimethylamino or phenyl whichis optionally mono- or disubstituted by halogen, amino or hydroxyl,

R² represents hydroxyl, alkoxy which has 1 to 3 carbon atoms and isoptionally substituted by hydroxyl, methoxy, amino or dimethylamino,benzyloxy or (5-methyl-2-oxo- 1,3-dioxol-4-yl)-methyloxy,acetoxymethyloxy, pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy,3-acetoxy-2-oxo-butyloxy, nitromethyl or dialkoxycarbonylmethyl having 1to 2 carbon atoms in each alkyl part,

R⁹ represents hydrogen or alkyl which has 1 to 3 carbon atoms and isoptionally substituted by methoxy, hydroxyl or-halogen,

R¹¹ represents hydrogen, CH₃, CH₂ F or═CH₂,

X¹ represents hydrogen, halogen or nitro,

X² represents hydrogen, halogen, amino, hydroxyl, methoxy, mercapto,methyl, halogenomethyl or vinyl,

A represents N or C--R⁷, wherein

R⁷ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ orC.tbd.CH, or together with R¹ can also form a bridge having thestructure --*O--CH₂ --CH--CH₃, --*S--CH₂ --CH₂ --, --*S--CH₂ --CH--CH₃,--*CH₂ --CH₂ --CH--CH₃ or --*O--CH₂ --N--R⁸, wherein the atom labelledwith * is linked to the carbon atom of A and wherein

R⁸ denotes hydrogen, methyl or formyl, and

D represents N or C--R¹⁰, wherein

R¹⁰ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂ or CH₃, or togetherwith R⁹ can also form a bridge having the structure --*O--CH₂ --,--*NH--CH₂ --, --*N(CH₃)--CH₂ --, --*N(C₂ H₅)--CH₂ --, --*N(C₃ H₅)--CH₂-- or --*S--CH₂ --, wherein the atom labelled with * is linked to thecarbon atom of D, and

T denotes a radical of the formula ##STR2## wherein B represents(CH₂)_(m) --NR³ R⁴ or (CH₂)_(m) --OR⁵, wherein

m represents 0 or 1,

R³ represents hydrogen, alkyl which has 1 to 3 carbon atoms and isoptionally substituted by hydroxyl, acyl having 1 to 3 carbon atoms oralkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part,

R⁴ represents hydrogen or methyl and

R⁵ represents hydrogen or methyl and

R⁶ represents hydrogen or methyl,

and pharmaceutically usable hydrates and acid addition salts thereof, aswell as the alkali metal, alkaline earth metal, silver and guanidiniumsalts of the underlying carboxylic acids, have a high antibacterialaction, in particular against Gram-positive bacteria, coupled with agood tolerability.

Preferred compounds of the formula (I) are those in which

Q denotes a radical of the formulae ##STR3## wherein R¹ represents alkylwhich has 1 to 4 carbon atoms and is optionally mono- or disubstitutedby halogen, atkenyl having 2 to 3 carbon atoms, cycloalkyl which has 3or 4 carbon atoms and is optionally substituted by 1 fluorine atom,bicyclo 1.1.1!pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl, methylaminoor phenyl which is optionally mono- or disubstituted by fluorine, aminoor hydroxyl,

R² represents hydroxyl, alkoxy having 1 to 2 carbon atoms, benzyloxy or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy,

R⁹ represents hydrogen or alkyl which has 1 to 2 carbon atoms and isoptionally mono- to trisubstituted by fluorine,

X¹ represents fluorine or chlorine,

X² represents hydrogen, halogen, amino, methyl, trifluoromethyl orvinyl,

A represents N or C--R⁷, wherein

R⁷ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ orC.tbd.CH, or together with R¹ can also form a bridge having thestructure --*O--CH₂ --CH--CH₃, --*S--CH₂ --CH₂ --, --*CH₂ --CH--CH₃ or--*O--CH₂ --N--R⁸, wherein the atom labelled with * is linked to thecarbon atom of A, and wherein

R8 denotes hydrogen or methyl, and

D represents N or C--R¹⁰, wherein

R¹⁰ represents hydrogen, fluorine, chlorine, CF₃, OCH₃ or CH₃, ortogether with R⁹ can also form a bridge having the structure --O--CH₂--, --*N(CH₃)--CH₂ --, --*N(C₂ H₅)--CH₂ --, --*N(C₃ H₅)--CH₂ -- or--*S--CH₂ --, wherein the atom labelled with * is linked to the carbonatom of D, and

T denotes a radical of the formula ##STR4## wherein B represents --NR³R⁴ or --OH wherein

R³ represents hydrogen or methyl,

R⁴ represents hydrogen or methyl and

R⁶ represents hydrogen

and pharmaceutically usable hydrates and acid addition salts thereof andthe alkali metal, alkaline earth metal, silver and guanidinium salts ofthe underlying carboxylic acids.

Compounds of the formula (I) which are particularly preferred are thosein which

Q denotes a radical of the formula ##STR5## wherein R¹ represents alkylwhich has 1 to 4 carbon atoms and is optionally mono- or disubstitutedby fluorine, vinyl, cyclopropyl which is optionally substituted by 1fluorine atom or phenyl which is optionally mono- or disubstituted byfluorine,

R² represents hydroxyl, alkoxy having 1 to 2 carbon atoms or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy,

X¹ represents fluorine,

X² represents hydrogen, fluorine, amino, methyl or vinyl,

A represents N or C--R⁷, wherein

R⁷ represents hydrogen, fluorine, chlorine, bromine, CF₃, OCH₃, OCHF₂,CH₃, CN, CH═CH₂ or C.tbd.CH, or together with R¹ can also form a bridgehaving the structure --*O--CH₂ --CH--CH₃ or --*O--CH₂ --N--R⁸ where theatom labelled with * is linked to the carbon atom of A, and wherein

R⁸ denotes hydrogen or methyl, and

T denotes a radical of the formula ##STR6## wherein B represents NH₂

R⁶ represents hydrogen,

and pharmaceutically usable hydrates and acid addition salts thereof andthe alkali metal, alkaline earth metal, silver and guanidinium salts ofthe underlying carboxylic acids.

It has furthermore been found that the compounds of the formula (I) areobtained by a process in which compounds of the formula (II)

    Y-Q                                                        (II)

in which

Q has the abovementioned meaning and

Y represents halogen, in particular fluorine or chlorine,

are reacted with compounds of the formula (III) ##STR7## in which B andR⁶ have the abovementioned meanings,

if appropriate in the presence of acid-trapping agents, and anyprotective groups are split off.

If, for example,6,7-difluoro-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid and (3aRS, 4RS)-2,3,3a,4,5,6hexahydro-1H-isoindol-4ylamine are usedas starting substances, the course of the reaction can be represented bythe following equation: ##STR8##

    DABCO 1,4-diazabicyclo 2,2,2!octane

The compounds of the formula (II) used as starting compounds are knownor can be prepared by known methods. They can be employed, whereappropriate, either as racemic or as enantiomerically pure compounds.Examples which may be mentioned are:

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 1-cyclopropyl-6,7-difluoro-1,4-dihydrooxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4dihydro-4-oxo-3-quinolinecarboxylicacid,5-bromo-1-(2,4-difluoro-phenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylicacid, 6,7-difluoro-1-ethyl-1,4dihydro-4-oxo-3-quinolinecarboxylic acid,7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,7-chloro-6-fluoro-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(2-fluoroethyl)-1,4dihydro-4-oxo-3-quinoline-carboxylicacid,7-chloro-6-fluoro-1,4-dihydro-1-methoxy-4-oxo-3-quinolinecarboxylicacid, 7-chloro-6-fluoro-1,4dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid,6,7-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid,7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate,ethyl1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-oxo-3-quinolinecarboxylate,9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido- 1,2,3-de!1,4!benzoxacine-6-carboxylic acid,8,9-difluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoij!-quinolicine-2-carboxylic acid,7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, ethyl7-choro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate,6,7,8-trifluoro-1,4-dihydro-1-methyl-amino-4-oxo-3-quinolinecarboxylicacid, 1-amino-6,7,8-trifluoro-1,4-dihyro-4-oxo-3-quiolinecarboxylicacid,6,7,8-trifluoro-1,4-dihydro-1-dimethylamino-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylicacid,7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,7-chloro-6-fluoro-1-(2,4difluorophenyl)-1,4-dihydro-4oxo-3-quinolinecarboxylicacid,6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylicacid,7-chloro-6fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylicacid,6,7-difluoro-1,4-dihydro-1-(3-oxetanyl)-4-oxo-3-quinolinecarboxylicacid,6,7,8-trifluoro-1,4-dihydro-1-(3-oxetanyl)-4-oxo-3-quinolinecarboxylicacid, 1-(bicyclo1.1.1!pent-1-yl)-6,7,8-trifluoro-1,4-dihydr-4-oxo-3quinolinecarboxylicacid,7-chloro-1-(1,1-dimethylpropargyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylicacid,7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, 6,7-difluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinolinecarboxylic acid,1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy-4-oxo-3-quinolinecarboxylicacid,1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid, ethyl7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate,1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylicacid,1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido 1,2,3-d,e!1,3,4!benzoxadiazine-6-carboxylic acid,8-amino-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido 1,2,3-d,e!1,3,4!benzoxadiazine-6-carboxylic acid, 7,8-difluoro-5-oxo-9,1-(N-methylimino)methano!-5H-thiazolo 3,2-a!-quinoline-4carboxylic acid,7,8-difluoro-5-oxo-9,1- (N-ethylimino)methano!-5H-thiazolo3,2-a!-quinoline4carboxylicacid,7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo3,2-a!-quinoline-1,4-carboxylic acid,7,8-difluoro-5-oxo-9,1-(epithiomethano)-5H-thiazolo3,2-a!-quinoline-1,4-carboxylic acid,7,8-difluoro-1-methyl-5-oxo-5H-thiazolo 3,2-a!-quinoline-4-carboxylicacid,8-bromo-6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-chloro-6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid,6,7,8-trifluoro-1-(cis-2-fluorocyclo-propyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,5,6,7,8-tetrafluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-8-methyl-1,4-oxo-3-quinolinecarboxylicacid,8-ethinyl-6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-8-difluoromethoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,6,7-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,5-amino-6,7,8-trifluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 8-bromo-6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 8-chloro-6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-1,4-oxo-3-quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 6,7,8-trifluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 5,6,7,8-tetrafluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-8-methyl-4-oxo-3-quinoline-carboxylicacid, 8-ethinyl-6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-8-difluoromethoxy-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-8-methoxy-4-oxo-3quinolinecarboxylicacid, 6,7-difluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid, 5-amino-6,7,8-trifluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro4-oxo-3quinolinecarboxylic acid,6,7-difluoro-4-oxo-4H- 1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid,6,7-difluoro-1-methyl-4-oxo-4H- 1,3!thiazeto3,2-a!quinoline-3-carboxylic acid, 6,7-difluoro1-fluoromethyl-4-oxo-4H-1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid.

The compounds of the formula (III) used as starting substances are new.They can be obtained by starting from a compound of the formula (1)##STR9## in which Z¹ denotes, for example, alkoxycarbonyl, P¹ denotes asuitable protective group on the nitrogen, for example benzyl,phenylethyl or alkoxycarbonyl having 1 to 4 carbon atoms in the alkylpart, and S¹ denotes hydrogen or methyl, and converting this into allylalcohols of the formula (2) ##STR10## by customary reduction processes,and converting these, using suitable oxidizing agents, such as, forexample, pyridine chlorochromate or dimethyl sulphoxideloxalylchloride/triethylamnine (Swern oxidation), into the intermediate of theformula (3) ##STR11## which is converted in a Wittig reaction orcomparable reaction into a compound of the formula (4) ##STR12## inwhich S² denotes hydrogen or methyl, and this is reacted with a compoundof the formula (5) ##STR13## in which Z² is, for example, cyano,alkoxycarbonyl, aryloxycarbonyl or nitro and S³ and S⁴ are identical ordifferent and represent hydrogen or methyl, in a cyclo additionreaction, to give compounds of the formula (6) formulated below in asimplified manner ##STR14## The compound of the formula (7) ##STR15##for example is separated off from the reaction mixture obtained bysuitable separation methods and, in the case where P¹ =benzyl orα-phenylethyl, is converted, by reaction with chioroformic acid estersor phosgene/alcohol, into a compound of the formula (8) ##STR16## inwhich P² represents alkoxycarbonyl having 1 to 4 carbon atoms in thealkyl part, which is converted, by suitable acid or basic hydrolysisconditions, into an acid of the formula (9) ##STR17## which isconverted, for example, by a Curtius degradation via an intermediatelyformed azide of the formula (10) ##STR18## into an isocyanate of theformula (11) ##STR19## which is converted by alcoholysis into a compoundof the formula (12) ##STR20## in which Z³ represents C₁ -C₄ -alkyl,which is converted, if appropriate, with an alkylating agent, forexample with methyl iodide, into a compound of the formula (13)##STR21## in which R³ denotes hydrogen or alkyl, and this is. convertedby hydrolysis with suitable acids or bases into a compound of theformula (14) ##STR22##

Compounds of the formula (14) correspond to the general formula (III).Compounds of the formula (III) in which B represents dialkylamino areobtained starting a compound (13) if the group COOZ³, which can denote,for example, a tert-butoxycarbonyl protective group, is split offselectively and the nitrogen function liberated is then alkylated.

After the Diels-Alder reaction, which leads to the compounds of theformula (6), the isomeric compounds with the reverse configuration onthe bridge-head carbon atom can also be isolated, and can be reacted ina manner corresponding to that already described for the series ofcompounds (6) to (14) to give compounds of the formula (15) ##STR23##Compounds of the formula (15) correspond to the general formula (III).

Compounds of the formula (III) in which B repesents hydroxymethyl areobtained if a compound of the formula (7) in which Z² representsalkoxycarbonyl is reduced, for example with complex hydrides, such asLiAlH₄.

Compounds of the formula (II) in which B represents aminomethyl areobtained if a cyano group in a compound of the formula (7) is convertedinto an aminomethyl group, for example via a reduction with complexhydrides, such as LiAlH₄, and this can optionally also be alkylated.Splitting off of the protective group P¹ follows.

Examples which may be mentioned of unsaturated bicyclic amines of theformula (III), which can be in the form both of diastereomerically pureor enantiomerically pure compounds and of diastereomer or enantiomermixtures, are:

2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,4-methyl-2,3,3a,4,5,6-hexahydro-1H-iso-indol-4-ylamine,5-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,6-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,7-methyl-2,3,3a,4,5,6-hexahydro-1H-iso-indol-4-ylamnine,4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-dimethylamino-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-aminomethyl-2,3,3a,4,5,6-hexahydro-1H-iso-indole,4-methylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-hydroxy-2,3,3a,4,5,6-hexahydro-1H-isoindole and4-hydroxymethyl-2,3,3a,4,5,6-hexahydro-1H-isoindole.

The enantiomerically pure starting compounds of the formula (III) can beprepared by the following processes:

1. The racemic bicyclic amines (III) can be reacted withenantiomerically pure acids, for example carboxylic acids or sulphonicacids, such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine,3-bromo-camphor-9-sulphonic acid, camphor-3-carboxylic acid, cis-camphoracid, camphor-10-sulphonic acid, O,O'-dibenzoyl-tartaric acid, D- orL-tartaric acid, mandelic acid, α-methoxy-phenylacetic acid,1-phenyl-ethanesulphonic acid or α-phenyl-succinic acid, to give amixture of the diastereomeric salts, which can be separated into thediastereomerically pure salts by fractional crystallization (see P.Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1).The enantiomerically pure amines can be liberated by treatment of thesesalts with alkali metal hydroxides or alkaline earth metal hydroxides.

2. In a manner similar to that described under 1., splitting ofracemates of the basic intermediate stages which occur duringpreparation of the racemic bicyclic amines can be carried out with theabovementioned enantiomerically pure acids.

3. Both the racemic amines (III) and some of the intermediate stagesleading to (III) can be separated by chromatography over chiral carriermaterials, if appropriate after acylation (see, for example, G.Blaschke, Angew. Chem. 92, 14 1980!).

4. The racemic amines (III) can also be converted by chemical linking tochiral acyl radicals into diastereomer mixtures, which can be separatedby distillation, crystallization or chromatography into thediastereomerically pure acyl derivatives, from which theenantiomerically pure amines can be isolated by hydrolysis. Examples ofreagents for linking with chiral acyl radicals are:α-methoxy-α-trifluoromethyl-phenylacetyl chloride, menthyl isocyanate,D- or L-α-phenyl-ethyl isocyanate, menthyl chloroformate andcamphor-10-sulphonyl chloride.

5. In the course of the synthesis of the bicyclic amines (III), chiralprotective groups can also be introduced instead of achiral protectivegroups. Diastereomer mixtures which can be separated are obtained inthis manner. For example, in the synthesis of the intermediate stage(7), any α-phenylethyl radical present can be in the R or Sconfiguration.

The reaction of (II) with (III), in which the compounds (III) can alsobe employed in the form of their salts, such as, for example, thehydrochlorides, is preferably carried out in a diluent, such as dimethylsulphoxide, N,N-dimethylformamide, N-methylpyrrolidone,hexamethyl-phosphoric acid trisamide, sulpholane, acetonitrile, water,an alcohol, such as methanol, ethanol, n-propanol, isopropanol or glycolmonomethyl ether, or pyridine. Mixtures of these diluents can also beused.

Acid-binding agents which can be used are all the customary inorganicand organic acid-binding agents. These include, preferably, the alkalimetal hydroxides, alkali metal carbonates, organic amines and amidines.Specific agents which may be mentioned as particularly suitable are:triethylamine, 1,4-diazabicyclo 2.2.2!octane (DABCO), 1,8-diazabicyclo5.4.0!undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a relatively wide range.In general, the reaction is carried out at between about 20° and 200°C., preferably between 80° and 160° C.

The reaction can be carried out under normal pressure, but also underincreased pressure. In general, it is carried out under pressures ofbetween about 1 and 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention, 1 to 15 mol,preferably 1 to 5 mol, of the compound (III) are employed per mole ofcompound (II).

Free amino groups can be protected by a suitable amino protective group,such as, for example, by the tert-butoxycarbonyl radical or anazomethine protective group, during the reaction and liberated againwhen the reaction has ended.

The preparation of compounds of the formula (I) according to theinvention in which R² represents CH₂ NO₂ or dialkoxycarbonylmethyl canalso be carried out by reacting a compound of the formula (I) in whichR² represents OH with an activating agent, such as carbonyldiimidazole,in a solvent, such as tetrahydrofran, methylene chloride or chloroform,and then reacting the product with a CH-acid compound, such asnitromethane or dialkyl malonates. This reaction is preferably carriedout in a solvent, such as tetrahydroftran, in the presence of a base(sodium hydride, potassium carbonate or sodium carbonate).

The preparation of compounds of the formula (I) according to theinvention in which X² denotes NH₂ is also carried out by reaction ofcompounds of the formula (I) in which X² denotes F with ammonia in polarsolvents, such as dimethyl sulphoxide, at temperatures from 50° C. to120° C. under normal pressure, or by heating in an autoclave. Compoundsof the formula (1) according to the invention in which A denotes C--OCH₃are also prepared by reaction of compounds of the formula (I) in which Adenotes C-F with alkali metal methylates, such as, for example, sodiummethylate or potassium methylate, in solvents, such as, for example,dimethylformamide, glycol dimethyl ether, dioxane, tetrahydrofiran,dimethyl sulphoxide, hexamethylphosphoric acid trisamide or alcohols, attemperatures from 20° C. to 150° C. If low-boiling solvents are used,the reaction can also be carried out in an autoclave under pressure. Thereaction can be accelerated and carried out at a lower temperature byaddition of crown ethers, such as, for example, 15-crown-5 or18-crown-6.

To prepare the esters according to the invention, the underlyingcarboxylic acid is preferably reacted in excess alcohol in the presenceof strong acids, such as sulphuric acid, anhydrous hydrogen chloride,methanesulphonic acid, p-toluenesulphonic acid or acid ion exchangers,at temperatures of about 20° to 180 ° C., preferably about 60° to 120 °C. The water of reaction formed can also be removed by azeotropicdistillation with chloroform, carbon tetrachloride or toluene.

The esters can also advantageously be prepared by heating the underlyingacid with dimethylformamide dialkyl acetal in a solvent, such asdimethylformamide.

The esters used as prodrugs, such as, for example, the(5-methyl-2-oxo-1,3-dioxol4-yl-methyl) ester, are obtained by reactingan alkali metal salt of the underlying carboxylic acid, which canoptionally be protected by a protective group on the N atom, with4-bromomethyl- or 4-chloromethyl-5-methyl-1,3-dioxol-2-one in a solvent,such as dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone,dimethyl sulphoxide or tetramethylurea, at temperatures of about 0° to100° C., preferably 0° to 50° C.

The acid addition salts of the compounds according to the invention areprepared in the customary manner, for example by dissolving in excessaqueous acid and precipitating the salt vath a water-miscible solvent,such as methanol, ethanol, acetone or acetonitrile. It is also possibleto heat an equivalent amount of betaine and acid in water or an alcohol,such as glycol monomethyl ether, and then to evaporate the mixture todryness or to filter off the precipitated salt with suction.Pharmaceutically usable salts are to be understood as meaning, forexample, the salts of hydrochloric acid, sulphuric acid, acetic acid,glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid,2-hydroxyglutaric acid, methanesulphonic acid, 4-toluenesulphonic acid,galacturonic acid, glucuronic acid, 5-oxotetrahydrofuran-2-carboxylicacid, embonic acid, glutamic acid or aspartic acid.

The alkali metal and alkaline earth metal salts of the carboxylic acidsaccording to the invention are obtained, for example, by dissolving thebetaine in excess alkali metal hydroxide solution or alkaline earthmetal hydroxide solution, filtration to remove the undissolved betaineand evaporation of the filtrate to dryness. The sodium, potassium andcalcium salts are pharmaceutically suitable. The corresponding silversalts are obtained by reaction of an alkali metal salt or alkaline earthmetal salt with a suitable silver salt, such as silver nitrate.

In addition to the active compounds mentioned in the examples, theactive compounds mentioned below and those listed in the followingtables can also be prepared, and can exist either as racemates or asenantiomerically pure compounds, or else where appropriate asdiastereomer mixtures or as diastereomerically pure compounds:

8-(3aRS,4RS)-4-Amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-7-fluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo3,2-a!quinoline-4-carboxylic acid, 7-fluoro-8-(3aRS,4RS)-4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-5-oxo-9,1-(epoxymethano)-5H-thiazolo3,2-a!quinoline-4-carboxylic acid,8-(4-amninomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-7-fluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo3,2-a!quinoline-4-carboxylic acid,7-fluoro-8-(4-methylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-5-oxo-9,1-(epoxymethano)-5H-thiazolo3,2-a!quinoline-4-carboxylic acid, 8-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-7-fluoro-5-oxo-9,1-(N-methyl-imino)methano!-5H-thiazolo 3,2-a!quinoline-4-carboxylicacid,7-fluoro-8-(3aRS,4RS)-4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-5-oxo-9,1-(N-methyl-imino)methano!-5H-thiazolo 3,2-a!quinoline-4-carboxylic acid,8-(4-aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-7-fluoro-5-oxo-9,1-(N-methyl-imino)methano!-5H-thiazolo 3,2-a!quinoline-4-carboxylic acid,7-fluoro-8-(4-methylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-5-oxo-9,1-(N-methyl-imino)methano!-5H-thiazolo 3,2-a!quinoline-4-carboxylic acid,10-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,3,4!benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-10-(3aRS,4RS)-4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,3,4!benzoxadiazine-6-carboxylic acid, 10-(3aRS,4RS)-4-anino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,3,4!benzoxadiazine-6-carboxylic acid, 8-amino-10-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,3,4!benzoxadiazine-6-carboxylic acid,10-(4-dimethylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,3,4!benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-10-(3aRS,4RS)-4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,4!benzoxazine-6-carboxylic acid,10-(4-aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,4!benzoxazine-6-carboxylic acid, 8-amino-10-(3aRS,4RS)-4-anino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,4!benzoxazine-6-carboxylic acid, 10-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-3-7-oxo-2,3-dihydro-7H-pyrido1,2,3-d,e! 1,4!benzoxazine-6-carboxylic acid, 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-6-fluoro-4-oxo-4H-1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid, 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-6-fluoro-1-methyl-4-oxo-4H-1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid, 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-6-fluoro-1-fluoromethyl-4-oxo-4H-1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid, 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-3-nitroacetyl-4-oxo-1,4dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-8-methoxy-3-nitroacetyl-4-oxo-1,4-dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6,8-difluoro-3-nitroacetyl-4-oxo-1,4-dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-8-chloro-6-fluoro-3-nitroacetyl-4-oxo-1,4-dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-4-oxo-1,4dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-3-(diethoxycarbonyl)acetyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-3-(diethoxycarbonyl)acetyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline,7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-8-chloro-1-cyclopropyl-3-(diethoxycarbonyl)aectyl-6-fluoro-4-oxo-1,4-dihydroquinoline,10- (3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-2,3-dihydro-3(S)-methyl-7-oxo-7H-pyrido 1,2,3-d,e!1,4!benzoxazine-6-carboxylic acid, 10-(3aSR,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-9-fluoro-2,3dihydro-3(S)-methyl-7-oxo-7H-pyrido 1,2,3-d,e!1,4!benzoxazine-6-carboxylic acid, 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-8-fluoro-1,4-dihydo-4-oxo-3-quinolinecarboxylicacid and 7-(3aSR,4RS)-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

                  TABLE I                                                         ______________________________________                                         ##STR24##                                                                    T*       A             X.sup.2     R.sup.2                                    ______________________________________                                        T.sup.I  CH            CH.sub.3    H                                          T.sup.I  CF            F           H                                          T.sup.I  CF            NH.sub.2    H                                          T.sup.I  CCH.sub.3     H           H                                          T.sup.I  COCH.sub.2 F  H           H                                          T.sup.I  N             H           C.sub.2 H.sub.5                            T.sup.I  CF            CHCH.sub.2  H                                          T.sup.I  CF            NH.sub.2    C.sub.2 H.sub.5                            T.sup.I  CF            H           C.sub.2 H.sub.5                            T.sup.I  CCl           H           C.sub.2 H.sub.5                            T.sup.I  CCCH          H           C.sub.2 H.sub.5                            T.sup.I  CCHCH.sub.2   H           H                                          T.sup.I  CF            Br          C.sub.2 H.sub.5                            T.sup.I  CCF.sub.3     H           H                                          T.sup.I  CCH.sub.3     F           H                                          T.sup.I  CCF.sub.3     NH.sub.2    H                                          T.sup.I  COCH.sub.3    H           C.sub.2 H.sub.5                            ______________________________________                                         *T.sup.I = (3aRS, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl    

                  TABLE 2                                                         ______________________________________                                         ##STR25##                                                                    T*     A          X.sup.2 R.sup.1      R.sup.2                                ______________________________________                                        T.sup.I                                                                              CH         H       C(CH.sub.3).sub.3                                                                          H                                      T.sup.II                                                                             CH         H       C(CH.sub.3).sub.3                                                                          H                                      T.sup.I                                                                              N          H       C(CH.sub.3).sub.3                                                                          H                                      T.sup.I                                                                              N          CH.sub.3                                                                              C(CH.sub.3).sub.3                                                                          H                                      T.sup.II                                                                             N          H       C(CH.sub.3).sub.3                                                                          H                                      T.sup.I                                                                              CH         H       Fluoro-tert.-butyl                                                                         H                                      T.sup.II                                                                             CH         H       Fluoro-tert.-butyl                                                                         H                                      T.sup.I                                                                              N          H       Fluoro-tert.-butyl                                                                         H                                      T.sup.II                                                                             N          H       Fluoro-tert.-butyl                                                                         H                                      T.sup.I                                                                              COCH.sub.3 H       Fluoro-tert.-butyl                                                                         H                                      T.sup.I                                                                              CH         H       2,4-Difluorophenyl                                                                         H                                      T.sup.II                                                                             CH         H       2,4-Difluorophenyl                                                                         H                                      T.sup.I                                                                              CH         H       4-Fluorophenyl                                                                             H                                      T.sup.II                                                                             CH         H       4-Fluorophenyl                                                                             H                                      T.sup.I                                                                              N          H       2,4-Difluorophenyl                                                                         H                                      T.sup.II                                                                             N          H       2,4-Difluorophenyl                                                                         H                                      T.sup.I                                                                              N          H       2,4-Difluorophenyl                                                                         C.sub.2 H.sub.5                        ______________________________________                                         *T.sup.I = (3aRS, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl         T.sup.II = (3aRS,                                                             4RS)4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl                

                  TABLE 3                                                         ______________________________________                                         ##STR26##                                                                    T*     A         X.sup.2 R.sup.1       R.sup.2                                ______________________________________                                        T.sup.I                                                                              CH        H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.II                                                                             CH        H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.I                                                                              N         H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.II                                                                             N         CH.sub.3                                                                              Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.I                                                                              CF        H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.II                                                                             CF        H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.I                                                                              COCH.sub.3                                                                              H       Bicyclo 1.1.1!pent-1-yl                                                                     H                                      T.sup.II                                                                             COCH.sub.3                                                                              H       Bicyclo 1.1.1!pent-1-yI                                                                     H                                      T.sup.I                                                                              CH        H       3-Oxetanyl    H                                      T.sup.II                                                                             CH        H       3-Oxetanyl    H                                      T.sup.I                                                                              N         H       3-Oxetanyl    H                                      T.sup.II                                                                             N         H       3-Oxetanyl    H                                      T.sup.I                                                                              CF        H       3-Oxetanyl    H                                      T.sup.II                                                                             CF        H       3-Oxetanyl    H                                      T.sup.I                                                                              COCH.sub.3                                                                              H       3-Oxetanyl    H                                      T.sup.II                                                                             COCH.sub.3                                                                              H       3-Oxetanyl    H                                      T.sup.II                                                                             CH        H       4-Fluorophenyl                                                                              C.sub.2 H.sub.5                        ______________________________________                                         *T.sup.I = (3aRS, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl         T.sup.II = (3aRS,                                                             4RS)4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl                

                  TABLE 4                                                         ______________________________________                                         ##STR27##                                                                    T*         A             X.sup.2   R.sup.2                                    ______________________________________                                        T.sup.III  CH            H         H                                          T.sup.IV   CH            H         H                                          T.sup.III  CF            H         H                                          T.sup.IV   CF            H         H                                          T.sup.III  CCl           H         H                                          T.sup.IV   CCl           H         H                                          T.sup.III  COCH.sub.3    H         H                                          T.sup.IV   COCH.sub.3    H         H                                          T.sup.III  CCHF.sub.2    H         H                                          T.sup.IV   CCHF.sub.2    H         H                                          T.sup.III  CCF.sub.3     H         H                                          T.sup.IV   CCF.sub.3     H         H                                          T.sup.III  CCH.sub.3     H         H                                          T.sup.IV   CCH.sub.3     H         H                                          T.sup.III  CCHCH.sub.2   H         H                                          T.sup.IV   CCHCH.sub.2   H         H                                          T.sup.III  CCCH          H         H                                          T.sup.IV   CCCH          H         H                                          ______________________________________                                         *T.sup.III = 4aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl             T.sup.IV = 4amino-4-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl       

                  TABLE 5                                                         ______________________________________                                         ##STR28##                                                                    T*   A         X.sup.2 R.sup.2                                                ______________________________________                                        T.sup.III                                                                          CF        NH.sub.2                                                                              H                                                      T.sup.IV                                                                           CF        NH.sub.2                                                                              H                                                      T.sup.III                                                                          CF        F       H                                                      T.sup.IV                                                                           CF        F       H                                                      T.sup.III                                                                          N         H       H                                                      T.sup.IV                                                                           N         H       H                                                      T.sup.III                                                                          COCH.sub.3                                                                              H       H                                                      T.sup.IV                                                                           COCH.sub.3                                                                              H       H                                                      T.sup.III                                                                          COCH.sub.3                                                                              H       (5-Methyl-2-oxo-1,3-dioxol-4-yl)-methyl                T.sup.IV                                                                           COCH.sub.3                                                                              H       (5-Methyl-2-oxo-1,3-dioxol-4-yl)-methyl                T.sup.I                                                                            COCH.sub.3                                                                              H       (5-Methyl-2-oxo-1,3-dioxol-4-yl)-methyl                T.sup.II                                                                           COCH.sub.3                                                                              H       (5-Methyl-2-oxo-1,3-dioxol-4-yl)-methyl                T.sup.III                                                                          N         CH.sub.3                                                                              H                                                      T.sup.IV                                                                           N         CH.sub.3                                                                              H                                                      T.sup.I                                                                            CH        CH.sub.3                                                                              H                                                      T.sup.II                                                                           CH        CH.sub.3                                                                              H                                                      T.sup.III                                                                          CH        CH.sub.3                                                                              H                                                      T.sup.IV                                                                           CH        CH.sub.3                                                                              H                                                      ______________________________________                                         *T.sup.I = (3aRS, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl         T.sup.II = (3aRS,                                                             4RS)4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl                     T.sup.III = 4aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl              T.sup.IV = 4aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl          

                  TABLE 6                                                         ______________________________________                                         ##STR29##                                                                    T*         A           X.sup.2    R.sup.2                                     ______________________________________                                        T.sup.I    CH          H          H                                           T.sup.I    CF          H          H                                           T.sup.I    CCl         H          H                                           T.sup.I    CCH.sub.3   H          H                                           T.sup.I    COCH.sub.3  H          H                                           T.sup.I    N           H          H                                           T.sup.I    CF          F          H                                           T.sup.I    CF          NH.sub.2   H                                           T.sup.I    CF          H          C.sub.2 H.sub.5                             T.sup.I    CCl         H          C.sub.2 H.sub.5                             T.sup.II   CH          H          H                                           T.sup.II   CF          H          H                                           T.sup.II   CCl         H          H                                           T.sup.II   CCH.sub.3   H          H                                           T.sup.II   COCH.sub.3  H          H                                           T.sup.II   N           H          H                                           T.sup.II   CF          F          H                                           ______________________________________                                         *T.sup.I = (3aRS, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl         T.sup.II = (3aRS,                                                             4RS)4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl                

                  TABLE 7                                                         ______________________________________                                         ##STR30##                                                                    T*         A           X.sup.2    R.sup.2                                     ______________________________________                                        T.sup.III  CH          H          H                                           T.sup.III  CF          H          H                                           T.sup.III  CCl         H          H                                           T.sup.III  CCH.sub.3   H          H                                           T.sup.III  COCH.sub.3  H          H                                           T.sup.III  N           H          H                                           T.sup.III  CF          F          H                                           T.sup.III  CF          NH.sub.2   H                                           T.sup.III  CF          H          C.sub.2 H.sub.5                             T.sup.III  CCl         H          C.sub.2 H.sub.5                             T.sup.IV   CH          H          H                                           T.sup.IV   CF          H          H                                           T.sup.IV   CCl         H          H                                           T.sup.IV   CCH.sub.3   H          H                                           T.sup.IV   COCH.sub.3  H          H                                           T.sup.IV   N           H          H                                           T.sup.IV   CF          F          H                                           ______________________________________                                         *T.sup.III = 4aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl             T.sup.IV = 4amino-4-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl       

                  TABLE 8                                                         ______________________________________                                         ##STR31##                                                                    T*         A            X.sup.2   R.sup.2                                     ______________________________________                                        T.sup.V    CH           H         H                                           T.sup.V    CF           H         H                                           T.sup.V    CCl          H         H                                           T.sup.V    CCH.sub.3    H         H                                           T.sup.V    COCH.sub.3   H         H                                           T.sup.V    N            H         H                                           T.sup.V    CF           F         H                                           T.sup.V    CF           NH.sub.2  H                                           T.sup.V    CF           H         C.sub.2 H.sub.5                             T.sup.V    CCl          H         C.sub.2 H.sub.5                             T.sup.VI   CH           H         H                                           T.sup.VI   CF           H         H                                           T.sup.VI   CCl          H         H                                           T.sup.VI   CCH.sub.3    H         H                                           T.sup.VI   COCH.sub.3   H         H                                           T.sup.VI   N            H         H                                           T.sup.VI   CF           F         H                                           ______________________________________                                         *T.sup.V = 4Methylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl         T.sup.VI = 4Ethylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl     

                  TABLE 9                                                         ______________________________________                                         ##STR32##                                                                    T*    A        X.sup.2   R.sup.1        R.sup.2                               ______________________________________                                        T.sup.VII                                                                           CH       H         Cyclopropyl    H                                     T.sup.VII                                                                           CF       H         Cyclopropyl    H                                     T.sup.VII                                                                           CCl      H         Cyclopropyl    H                                     T.sup.VII                                                                           COCH.sub.3                                                                             H         Cyclopropyl    H                                     T.sup.VII                                                                           N        H         Cyclopropyl    H                                     T.sup.VII                                                                           N        H         C(CH.sub.3).sub.3                                                                            H                                     T.sup.VII                                                                           CH       H         (1R, 2S)-2-Fluorocyclopropyl                                                                 H                                     T.sup.VII                                                                           CF       H         (1R, 2S)-2-Fluorocyclopropyl                                                                 H                                     T.sup.VII                                                                           COCH.sub.3                                                                             H         (1R, 2S)-2-Fluorocyclopropyl                                                                 H                                     T.sup.VII                                                                           N        H         (1R, 2S)-2-Fluorocyclopropyl                                                                 H                                     T.sup.VII                                                                           CH       H         2,4-Difluorophenyl                                                                           H                                     T.sup.VII                                                                           N        H         2,4-Difluorophenyl                                                                           H                                     T.sup.VII                                                                           CH       H         4-Fluorophenyl H                                     T.sup.VII                                                                           CH       H         4-Fluorophenyl H                                     T.sup.VII                                                                           CH       H         Ethyl          H                                     T.sup.VII                                                                           CCH      H         Cyclopropyl    H                                     T.sup.VII                                                                           CF       CHCH.sub.2                                                                              Cyclopropyl    H                                     T.sup.VII                                                                           CF       F         Cyclopropyl    H                                     T.sup.VII                                                                           CF       NH.sub.2  Cyclopropyl    H                                     T.sup.VII                                                                           CH       CH.sub.3  Cyclopropyl    H                                     ______________________________________                                         *T.sup.VII = (3aSR, 4RS)4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl  

The compounds according to the invention have a potent antibiotic actionand display a broad antibacterial spectrum against Gram-positive andGram-negative germs, above all including those which are resistant tovarious antibiotics, such as, for example, penicillins, cephalosporins,anunoglycosides, sulphonamides, tetracyclines and against commerciallyavailable quinolones, coupled with a low toxicity. The compoundsaccording to the invention are distinguished in particular by the factthat they have lower interactions with mammalian DNA compared with thecompounds according to the prior art.

These valuable properties enable them to be used as chemotherapeuticactive compounds in medicine and in veterinary medicine.Furthermore,they can be used as substances for the preservation of inorganic andorganic materials, for example polymers, lubricants, paints, fibres,leather, paper and wood, and of foodstuffs and water.

The compounds according to the invention are active against a very broadspectrum of microorganisms. Gram-negative and Gram-positive bacteria andbacteria-like microorganisms can be combated and the diseases caused bythese pathogens can be prevented, alleviated and/or cured with the aidof these compounds.

The compounds according to the invention are distinguished by an strongaction against dormant germs. The compounds have a potent bactericidalaction on dormant bacteria, that is to say bacteria which show nodetectable growth. This relates not only to the amount to be employed,but also to the rate of destruction. Such results have been found onGram-positive and Gram-negative bacteria, in particular onStaphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis andEscherichia coli.

The compounds according to the invention are particularly active againsttypical and atypical Mycobacteria and Helicobacter pylori, and alsoagainst bacteria-like microorganisms, such as, for example, Mycoplasmaand Rickettsia They are therefore particularly suitable in human andveterinary medicine for the prophylaxis and chemotherapy of local andsystemic infections caused by these pathogens.

The compounds are furthermore particularly suitable for combatingprotozoonoses and helminthoses.

The compounds according to the invention can be used in variouspharmaceutical formulations. Preferred pharmaceutical formulations whichmay be mentioned are tablets, coated tablets, capsules, pills, granules,suppositories, solutions, suspensions and emulsions, pastes, ointments,gels, creams, lotions, powders and sprays.

The compounds according to the invention can also be linked to β-lactamderivatives, such as, for example, cephalosporins or penems, by covalentbonds to give so-called dual action derivatives.

Tables 9 and 10 show the minimum inhibitory concentrations (MIC values),as a measure of the antibacterial activity, and the ID₅₀ values, as ameasure of the interactions with mammalian DNA of a substance, both forcompounds according to the invention and for reference compounds fromthe prior art (EP 520 240). These data demonstrate that the compoundsaccording to the invention show less interactions with mammalian DNA,coupled with a high antibacterial activity.

The minimum inhibitory concentrations (MIC) were determined by a seriesdilution method on Iso-Sensitest agar (Oxoid). For each test substance,a series of agar plates each comprising concentrations of the activecompound decreasing by double dilution in each case was prepared. Theagar plates were inoculated with a multipoint inoculator (Denley).Overnight cultures of the pathogens which had been diluted beforehandsuch that each inoculation point comprised about 10⁴ colony-formingparticles were used for the inoculation. The inoculated agar plates wereincubated at 37° C. and the germ growth was read off after about 20hours. The MIC value (μg/ml) indicates the lowest active compoundconcentration at which no growth was detectable with the naked eye.

The ID₅₀ is understood as meaning the concentration of a substance atwhich DNA synthesis in cells from ovaries of the Chinese hamster(CHO-KI) is inhibited by 50%. This value is determined after incubationof the corresponding substances in decreasing dilution stages overdefined periods of time. For this, the DNA synthesis in CHO-KI cells isdetermined in comparison with controls by means of fluorophotometricmethods.

                  TABLE 9                                                         ______________________________________                                        MIC values (μg/ml) and ID.sub.50 values of active compounds according      to the                                                                        invention                                                                                  Example                                                          Species  Strain    1        2     3      4                                    ______________________________________                                        E. coli  Neumann   ≦0.015                                                                          ≦0.015                                                                       ≦0.015                                                                        ≦0.015                        Staph. aureus                                                                          133       ≦0.015                                                                          ≦0.015                                                                       ≦0.015                                                                        ≦0.015                        Staph. aureus                                                                          ICB 25701 ≦0.015                                                                          0.125 ≦0.015                                                                        0.03                                 Ps. aeruginosa                                                                         Walter    0.125    1     0.5    0.25                                 ID.sub.50 (μg/ml)                                                                             4        2     0.1    2                                    ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        MIC values (μg/ml) and ID.sub.50 values of active compounds from the       prior                                                                         art                                                                                          Examples from EP 520 240*)                                     Species   Strain     17B      19      18A                                     ______________________________________                                        E. coli   Neumann    ≦0.015                                                                          ≦0.015                                                                         ≦0.015                           Staph. aureus                                                                           133        ≦0.015                                                                          ≦0.015                                                                         ≦0.015                           Staph. aureus                                                                           ICB 25701  0.03     1       ≦0.015                           Ps. aeruginosa                                                                          Walter     0.25     1       0.25                                    ID.sub.50 (μg/ml) 0.01     1       0.06                                    ______________________________________                                         *)Reference compounds from EP 520 240:                                        17 B:                                                                         7(4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6,8-difluo    o-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,                                19:                                                                           7(4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6-fluoro-1    4-dihydro-4-oxo-3-quinolinecarboxylic acid,                                    18A:                                                                          7(4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-8-chloro-1-cyclopropyl-6    fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid                       

PREPARATION OF THE INTERMEDIATE PRODUCTS EXAMPLE Z 1 ##STR33## 87.0 g(0.38 mol) of ethyl 1-benzyl-2,5-dihydro-1H-pyrrole-3-carboxylate areinitially introduced into 430 ml of tetrahydroftran, the mixture iscooled to -70° C., and 1200 ml of a 1 molar solution ofdiisobutylaluminium hydride in hexane are added dropwise. The mixture issubsequently stirred at -70° C. for 3 hours and at room temperature fora further 15 hours. It is cooled to 0° C. and hydrolyeed by addition of390 ml of saturated ammonium chloride solution and 390 ml of 6 normalsulphuric acid. The aqueous phase is separated off, rendered basic withpotassium hydroxide and extracted several times with tert-butylmethylether. The combined organic extracts are dried, concentrated anddistilled.

Yield: 58.0 g (81% of theory) of1-benzyl-2,5-dihydro-3-hydroxymethyl-1H-pyrrole, Boiling point:120°-122° C./0.1 mbar, ¹ H-NMR (CDCl₃): δ 7.50-7.18 (m, 5H), 5.55 (m,1H), 4.10 (m, 2H), 3.80 (s, 2H), 3.70-3.35 ppm (m, 5H).

EXAMPLE Z 2 ##STR34## 64.3 g (0.49 mol) of oxalyl chloride are dissolvedin 580 ml of methylene chloride and the solution is cooled to -70° C.First a solution of 76.5 g of dimethyl sulphoxide in 174 ml of methylenechloride and then a solution of 58.0 g (0.31 mol) of1-benzyl-2,5-dihydro-3-hydroxymethyl-1H-pyrrole in 174 ml of methylenechloride, and subsequently 198 g of triethylaamine are added dropwise.The mixture is subsequently stirred for 30 minutes, heated to roomtemperature and poured onto 600 g of ice. The organic phase is separatedoff and the aqueous phase is rendered more strongly basic with potassiumcarbonate and extracted several times with methylene chloride. Thecombined organic phases are dried and concentrated and the residue isused for the next reaction without further purification.

Yield (crude): 59.5 g of 1-benzyl-2,5-dihydro-1H-pyrrole-3-carbaldehyde,¹ H-NMR (CDCl₃): δ 9.74 (s, 1H), 7.60-7.10 (m, 5H), 6.85 (m, 1H), 3.81(s, 2H), 3.80-3.60 ppm (m, 4H).

EXAMPLE Z 3 ##STR35## 129 g (0.36 mol) of methyltriphenylphosphoniumbromide are initially introduced into 828 ml of tetrahydrofa, themixture is cooled to -10° C., 111 g of a 23% strength n-butyllithiumsolution in hexane are added dropwise and the mixture is subsequentlystirred at -10° C. for 20 minutes and at -70° C. for 90 minutes. Asolution of 59.1 g (0.31 mol) of1-benzyl-2,5-dihydro-1H-pyrrole-3-carbaldehyde in 197 ml oftetrahydrofiran is then added dropwise and the mixture is warmed to roomtemperature overnight. The mixture is poured into 2000 ml of a saturatedsodium chloride solution and extracted several times with petroleumether. The combined organic phases are dried, the triphenylphosphineoxide which precipitates is filtered off with suction, the filtrate isconcentrated again and the residue is used for the next reaction withoutfurther purification.

Yield: 57.0 g (82% of theory, purity 83% according to GC) of1-benzyl-2,5-dihydro-3-vinyl-1H-pyrrole, ¹ H-NMR (CDCl₃): δ 7.40-7.20(m, 5H), 6.48 (dd, 1H), 5.73 (s, 1H), 5.03 (dd, 2H), 3.85 (s, 2H), 3.58ppm (s, 4H).

EXAMPLE Z 4 ##STR36## 20.0 g (0.08 mol, 73% pure) of1-benzyl-2,5-dihydro-3-vinyl-1H-pyrrole, dissolved in 180 ml ofmethylene chloride, are mixed with 13.8 g of sodium carbonate and themixture is cooled to 0° C. A solution of 12.3 g of methyl chloroformatein 40 ml of methylene chloride is added dropwise and the mixture issubsequently stirred at room temperature for 15 hours. The solid isfiltered off and washed out several times with methylene chloride, andthe filtrates are combined. They are washed with water, dried andconcentrated and the residue is chromatographed over silica gel with amixture of ethyl acetate and petroleum ether (1:10).

Yield: 7.70 g (46% of theory) of2,5-dihydro-1-methoxycarbonyl-3-vinyl-1H-pyrrole, ¹ H-NMR (CDCl₃): δ6.49 (dd, 1H), 5.80-5.67 (m, 1H), 5.25-5.00 (m, 2H), 4.35-4.15 (m, 4H),3.74 ppm (d, 3H).

EXAMPLE Z 5 ##STR37## 20.0 g (0.08 mol) of1-benzyl-2,5-dihydro-3-vinyl-1H-pyrrole are dissolved in 200 ml ofxylene, and a solution of 39.4 g (0.31 mol) of teributyl acrylate in 200ml of xylene is added. The mixture is heated under reflux overnight,cooled and concentrated.

Yield: 17.6 g (0.06 mol) of a mixture of four isomers which can beseparated by chromatography. Column chromatography over silica gel withmixtures of ethyl acetate and petroleum ether (1:30 to 1:5) allowstert-butyl (5RS,6RS)-8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylatetert-butyl(3aRS,4RS)-2-benzyl-2,3,3a,4,5,6-hexahydro-1H-isoindole-4-carboxylate!and tert-butyl (5RS,6SR)-8-benzyl-8-azabicyclo4.3.0!non-1-ene-5-carboxylatetert-butyl(3aRS,4SR)-2-benzyl-2,3,3a,4,5,6-hexahydro-1H-isoindole-4-carboxylate!to be separated off from the two tert-butyl 8-benzyl-8-azabicyclo4.3.0!non-1-ene4-carboxylates formed.

¹ H-NMR of the (5RS,6RS) isomer (CDCl₃): δ 7.40-7.20 (m, 5H), 5.40 (m,1H), 3.66 (q, 2H), 3.56 (dm, 1H), 3.29 (dd, 1H), 2.92 (dm, 1H),2.70-2.80 (m, 1H), 2.20-1.90 (m, 5H), 1.75-1.45 (m, 1H), 1.43 ppm (s,9H).

¹ H-NMR of the (5RS,6SR) isomer (CDCl₃): δ 7.42-7.20 (m, 5H), 5.43 (m,1H), 3.67 (q, 2H), 3.56 (dm, 1H), 3.06-2.70 (m, 3H), 2.42-1.95 (m, 4H),1.85-1.65 (m, 2H), 1.43 ppm (s, 9H).

EXAMPLE Z 6 ##STR38## 7.00 g (0.04 mol) of1-benzyl-2,5-dihydro-3-vinyl-1H-pyrrole are dissolved in 50 ml ofxylene, and a solution of 5.00 g (0.09 mol) of acrylonitrile in 50 ml ofxylene is added. The mixture is heated under reflux overnight, cooledand concentrated.

Yield: 3.7 g (41% of theory) of a mixture of four isomers which can beseparated by chromatography. Column chromatography over silica gel withmixtures of ethyl acetate and petroleum ether (1:30 to 1:5) allows8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylic acid nitrile to beseparated off from 8-benzyl-8-azabicyclo 4.3.0!non-1-ene-4-carboxylicacid nitrile.

¹ H-NMR of (5RS,6RS)-8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylicacid nitrile (CDCl₃): δ 7.40-7.20 (m, 5H), 5.45 (m, 1H), 3.78 (d, 1H),3.58 (d, 1H), 3.55 (dm, 1H), 3.22 (dd, 1H), 2.90 (dm, 1H), 2.80-2.65 (m,4H), 1.90-1.65 ppm (m, 1H).

EXAMPLE Z 7 ##STR39## 3.00 g (0.01 mol) of a mixture of8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylic acid nitrile and8-benzyl-8-azabicyclo 4.3.0!non-1-ene-4-carboxylic acid nitrile aredissolved in 20 ml of methylene chloride, the solution is stirred with1.93 g of sodium carbonate, and 2.00 g of ethyl chloroformate, dissolvedin 3 ml of methylene chloride, are added. The mixture is subsequentlystirred at room temperature for 15 hours and the solid is filtered offand rinsed several times with methylene chloride. The combined filtratesare washed with water, dried and concentrated and the residue ischromatographed over silica gel with a mixture of ethyl acetate andpetroleum ether (1:4).

Yield: 1.1 g (40% of theory) of a mixture of8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-4-carboxylic acid nitrileand 8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylic acidnitrile.

EXAMPLE Z 8 ##STR40## 23.0 g (0.07 mol) oftert-butyl(5RS,6RS)-8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylatein 180 ml of methylene chloride are mixed with 12.5 g (0.12 mol) ofsodium carbonate, the mixture is cooled to 0° C. and a solution of 11.9g (0. 12 g) of methyl cloroforyfate in 45 ml of methylene chloride isadded dropwise. After 30 minutes at 0° C., the mixture is warmed to roomtemperature and subsequently stirred overnight. The solid is filteredoff and washed out, the combined organic filtrates are washed withwater, dried and concentrated and the benzyl chloride formed during thereaction is removed by distillation.

Yield: 17.0 g (76% of theory) oftert-butyl(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylate, ¹ H-NMR (CDCl₃): δ 5.60 (m, 1H), 4.05-3.75(m, 3H), 3.70 (s, 3H), 2.90-2.72 (m, 2H), 2.60-2.42 (m, 2H), 2.35-2.10(m, 3H), 1.45 ppm (s, 9H).

EXAMPLE Z 9 ##STR41## 17.0 g (0.06 mol) of tert-butyl(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylateare initially introduced into 420 ml of methylene chloride, 120 ml oftrifluoroacetic acid are added dropwise and the mixture is subsequentlystirred at room temperature for 3 hours. It is concentrated, the residueis taken up again in methylene chloride and the mixture is washedseveral times with water. The residue is filtered over silica gel with amixture of cyclohexane and acetone (3:1).

Yield: 7.9 g (58% of theory) of (5RS,6RS)-8-methoxycarbonyl-8-azabicyclo4.3.0!non-1-ene-5-carboxylic acid, Melting point: 144°-147° C., ¹ H-NMR(CDCl₃): δ 10.5-9.20 (m, 1H), 5.65 (dm, 1H), 4.10-3.75 (m, 3H), 3.71 (s,3H), 3.00-2.90 (m, 1H), 2.90-2.80 (m, 1H), 2.30-2.14 (m, 4H), 1.75-1.65ppm (m, 1H).

EXAMPLE Z 10 ##STR42## 8.50 g (0.04 mol)of(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylicacid are initially introduced into 200 ml of toluene, and the mixture ismixed with 4.20 g of triethylamine and 12.5 g of diphenylphosphorylazide. The mixture is heated under reflux for 5 hours, the cooledsolution is poured onto ice-water and the organic phase is separated offand extracted several more times with toluene. The combined extracts aredried and concentrated and the residue is used for the followingreaction without further purification.

Crude yield: 10.6 g of a brown oil,(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-en-5-ylisocyanate,IR: 2250 cm⁻¹, ¹ H-NMR (CD₃ OD): δ 5.62 (m, 1H), 4.08-3.76 (m, 3H), 3.67(s, 3H), 3.42 (ddd, 1H), 2.96 (tm, 1H), 2.80-2.50 (m, 1H), 2.35-2.15 (m,2H), 2.02-1.83 (m, 1H), 1.65-1.40 ppm (m, 1H).

EXAMPLE Z 11 ##STR43## 10.6 g of crude(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-en-5-yl isocyanateare dissolved in 200 ml of methanol and the solution is heated underreflux for 15 hours. The cooled mixture is concentrated and the residueis chromatographed over silica gel with a mixture of cyclohexane andacetone (3:1).

Yield: 6.11 g (64% of theory, based on the acid)(5RS,6RS)-5-methoxycarbonylamino-8-azabicyclo4.3.0!non-1-ene-8-carboxylate, Melting point: 118°-121° C., ¹ H-NMR(CDCl₃): δ 5.59 (d, 1H), 4.65 (m, 1H), 4.07-3.85 (m, 3H), 3.72 (s, 3H),3.68 (s, 3H), 3.50 (m, 1H), 3.08 (qm, 1H), 2.52 (m, 1H), 2.35-2.15 (m,2H), 2.05-1.95 (m, 1H), 1.53-1.41 ppm (m, 1H).

EXAMPLE Z 12 ##STR44## 6.00 g (0.02 mol) of methyl(5RS,6RS)-5-methoxycarbonylamino-8-azabicyclo4.3.0!non-1-ene-8-carboxylate are dissolved in 20 ml of ethanol, and 400g of a saturated barium hydroxide solution are added. The mixture isheated under reflux for two days and cooled, the barium carbonate whichhas precipitated out is filtered off and the filtrate is extractedseveral times with chloroform. The organic phases are dried andconcentrated.

Yield: 3.20 g (98% of theory) of(5RS,6RS)-5-amino-8-azabicyclo4.3.0!non-1-ene (3aRS,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol4ylamine!,¹ H-NMR (CDCl₃): δ 5.46 (m, 1H), 3.72-3.55 (m, 1H), 3.55-3.33 (m, 2H),2.65-2.36 (m, 2H), 2.33-2.05 (m, 3H), 1.91-1.76 (m, 1H), 1.64 (s, 3H),1.53-1.30 ppm (m, 1H).

EXAMPLE Z 13 ##STR45## 240 mg (7.87 mmol) of 80% pure sodium hydride areinitially introduced into 10 ml of tetrahydrofuran, 1.00 g of methyl(5RS,6RS)-5-methoxycarbonylamino-8-azabicyclo4.3.0!non-1-ene-8-carboxylate, dissolved in 10 ml of tetahydrofuran, isadded dropwise and the mixture is heated under reflux for 30 minutes. Itis allowed to cool to room temperature, 1.12 g (7.87 mmol) of methyliodide are added and the mixture is heated under reflux for 15 hours. Itis then cooled to room temperature, excess sodium hydride is decomposedwith a little water, and the mixture is poured onto ice-water andextracted several times with ethyl acetate.

Yield: 1.00 g (95% of theory). (5RS,6RS) isomer: ¹ H-NMR (CDCl₃): δ 5.58(d, 1H), 4.08-3.89 (m, 3H), 3.85-3.75 (m, 1H), 3.72 (s, 3H), 3.70 (s,3H), 3.02 (t, 1H), 2.90-2.82 (m, 1H), 2.84 (s, 3H), 2.35-2.25 (m, 2H),1.80-1.72 ppm (m, 2H).

EXAMPLE Z 14 ##STR46## 1.5 g (6 mmol) of methyl(5RS,6RS)-5-(N-methoxycarbonyl-N-methyl-amino)-8-azabicyclo4.3.0!non-1-ene-8-carboxylate are dissolved in 10 ml of ethanol, and 130g of a saturated barium hydroxide solution are added. The mixture isheated under reflux for two days and cooled, the barium carbonate whichhas precipitated out is filtered off and the filtrate is extractedseveral times with chloroform. The combined organic phases are dried andconcentrated. 0.6 g of a brown oil which is chromatographed over silicagel with a mixture of methylene chloride/methanol/aqueous ammonia(14:5:1) is obtained.

Yield: 0.1 g (9% of theory) of (5RS,6RS)-5-methylamnino-8-azabicyclo4.3.0!non-1-ene(3aRS,4RS)-4methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindole!, ¹ H-NMR(CDCl₃ /CD₃ OD): δ 5.88 (m, 1H), 4.02-3.85 (m, 3H), 3.18-3.04 (m, 3H),3.75 (s, 3H), 2.48-2.23 (m, 3H), 1.82-1.72 ppm (m, 1H).

EXAMPLE Z 15 ##STR47## 17.0 g (0.05 mol) of tert-butyl(5RS,6SR)-8-benzyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylate aredissolved in 140 ml of methylene chloride, the solution is mixed with9.4 g (0.09 mol) of sodium carbonate, the mixture is cooled to 0° C. anda solution of 8.9 g (0.09 mol) of methyl chloroformate in 35 ml ofmethylene chloride is added dropwise. After 30 minutes at 0° C., themixture is warmed to room temperature and subsequently stirredovernight. The solid is filtered off and washed out, the combinedorganic filtrates are washed with water, dried and concentrated and thebenzyl chloride formed during the reaction is removed by distillation.

Yield: 4.9 g (32% of theory) of tert-butyl(5RS,6SR)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylate,¹ H-NMR (CDCl₃): δ 5.63 (m, 1H), 4.05-3.90 (m, 2H), 3.82-3.65 (m, 1H),3.71 (s, 3H), 3.29 (t, 1H), 2.95-2.75 (m, 2H), 2.39-1.92 (m, 3H),1.89-1.69 (m, 1H), 1.45 ppm (s, 9H).

EXAMPLE Z 16 ##STR48## 4.0 g (0.01 mol) of tert-butyl(5RS,6SR)-2-methoxycarbonyl-2-azabicyclo 4.3.0!non-4-ene-8-carboxylateare initially introduced into 100 ml of methylene chloride at 0° C., 30ml of trifluoroacetic acid are added dropwise and the mixture issubsequently stirred at room temperature for 3 hours. It isconcentrated, the residue is taken up again in methylene chloride andthe mixture is washed several times with water. The residue is filteredover silica gel with a mixture of cyclohexane and acetone (3:1).

Yield: 3.0 g (94% of theory) of (5RS,6SR)-8-methoxycarbonyl-8-azabicyclo4.3.0!non-1-ene-5-carboxylic acid, Melting point: 93°-95° C., ¹ H-NMR(CDCl₃): δ 10.5-9.50 (m, 1H), 5.65 (m, 1H), 4.08-3.90 (m, 2H), 3.85-3.70(m, 1H), 3.72 (s, 3H), 3.39 (t, 1H), 3.07-3.00 (m, 1H), 2.95-2.83 (m,1H), 2.35-2.24 (m, 1H), 2.13-2.01 (m, 2H), 1.88-1.79 ppm (m, 1H).

EXAMPLE Z 17 ##STR49## 3.0 g (0.01 mol) of(5RS,6SR)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-carboxylicacid are initially introduced into 50 ml of toluene, and the mixture ismixed with 1.4 g of triethylamine and 3.8 g of diphenylphosphoryl azide.It is heated at 60° C. for 8 hours, the cooled solution is poured ontoice-water and the organic phase is separated off and extracted severalmore times with toluene. The combined extracts are dried andconcentrated and the residue is used for the following reaction withoutfurther purification.

Crude yield: 5.2 g of a brown oil which comprises, as the mainconstituent, a mixture of (5RS,6SR)- and(5RS,6RS)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-en-5-yl isocyanate,IR: 2150 and 2250 cm⁻¹

EXAMPLE Z 18 ##STR50## 5.2 g of crude(5RS,6SR)-8-methoxycarbonyl-8-azabicyclo 4.3.0!non-1-ene-5-isocyanateare dissolved in 70 ml of methanol and the solution is heated underreflux for 15 hours. The cooled mixture is concentrated and the residueis chromatographed over silica gel with a mixture of cyclohexane andacetone (2:1).

Yield: 1.6 g (45% of theory, based on the acid) of methyl(5RS,6SR)-5-methoxycarbonylamino-8-azabicyclo4.3.0!non-1-ene-8-carboxylate, Melting point: 113°14 117° C., ¹ H-NMR(CDCl₃): δ 5,65 (m, 1H), 4.71 (m, 1H), 4.25 (m, 1H), 4.07-3.70 (m, 3H),3.69 (s, 3H), 3.65 (s, 3H), 3.50 (m, 1H), 3.08 (dt, 1H), 2.88 (m, 1H),2.22-2.05 (m, 2H), 2.00-1.87 (m, 1H), 1.75-1.64 ppm (m, 1H).

EXAMPLE Z 19 ##STR51## 1.20 g (0.005 mol) of methyl(5RS,6SR)-5-methoxycarbonylamino-8-azabicyclo4.3.0!non-1-ene-8-carboxylate are dissolved in 5 ml of ethanol, and 100g of a saturated barium hydroxide solution are added. The mixture isheated under reflux for two days and cooled, the barium carbonate whichhas precipitated out is filtered off and the filtrate is extractedseveral times with chloroform. The combined organic phases are dried andconcentrated.

Yield: 0.60 g (crude yield 92% of theory) of a brown oil:(5RS,6SR)-5-amino-8-azabicyclo 4.3.0!non-1-ene(3aSR,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylaminle!, ¹ H-NMR(CDCl₃): δ 5.55 (m, 1H), 3.49 (dd, 2H), 3.32 (m, 1H), 3.13 (m, 1H), 2.75(t, 1H), 2.47-2.59 (m, 1H), 2.10-1.88 (m, 2H), 1.92 (m, 3H), 1.73-1.53ppm (m, 2H).

PREPARATION OF THE ACTIVE COMPOUNDS EXAMPLE 1 ##STR52## 224 mg (2 mmol)of 1,4-diazabicyelo 2.2.2!octane and 152 mg (1.1 mmol) of(3aRS,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine are added to 283mg (1 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in a mixture of 2 ml of acetonitrile and 1 ml of dimethylformamideand the mixture is heated under reflux for 1 hour. It is concentrated invacuo, the residue is stirred with about 40 ml of water and, afterdrying at 70° C. under a high vacuum, the residue which has precipitatedout is purified by chromatography: silica gel, methylenechloride/methanol/17% strength aqueous ammonia (30:8:1).

Yield: 197 mg (49% of theory) of 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, Melting point: 205°-207° C. (with decomposition).

EXAMPLE 2 ##STR53##

Under conditions corresponding to those in Example1,1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid gives 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 210°-213° C. (with decomposition) in a yield of29%.

EXAMPLE 3 ##STR54##

Under conditions corresponding to those in Example 1,8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid gives 7-(3aRS,4RS)-4-amino2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid of melting point 181°-184° C. (with decomposition) in a yield of85%.

EXAMPLE 4 ##STR55##

Under conditions corresponding to those in Example 1, 6, 7,8-trifluoro-1-(cis-2-fluoro-cyclopropyl)-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid gives 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-6,8-difluoro-1-(cis-2-fluoro-cyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 210°-205° C. (with decomposition) in a yield of68%.

EXAMPLE 5 ##STR56##

Under conditions corresponding to those in Example 1,1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid gives 7-(3aRS,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihyro-4-oxo-3-quinolinecarboxylicacid of melting point 270°-274° C. (with decomposition) in a yield of77%.

EXAMPLE 6 ##STR57##

Under conditions corresponding to those in Example 1,1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo3-quinolinecarboxylicacidgives7- (3aRS,4RS)-4amino-2,3,3a,4,5,6-hexahydro1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid of melting point 236°-238° C. (with decomposition) in a yield of67%.

EXAMPLE 7 ##STR58## 332 mg (2.4 mmol) of(3aRS,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine are added to 283mg (1 mmol) of7-chloro-1-cyclopropyl-6-fluoro-1,4-dihyro-4-oxo-1,8-naphthyridine-3-carboxylicacid in 6 ml of acetonitrile and the mixture is heated at 50° C. for 1hour. The precipitate which has separated out is filtered off withsuction, washed with acetonitrile and purified by chromatography: silicagel, methylene chloridelmethanol/17% strength aqueous ammonia (30:8:1).

Yield: 76 mg (20% of theory) of 7-(3aRS)-4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid, Melting point: 263°-265° C. (with decomposition).

EXAMPLE 8 ##STR59##

Under conditions corresponding to those in Example 1,8-chloro-6,7-difluoro-1-(1R,2S)-2-fluoro-cyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid and (3aSR,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine give 7-(3aSR,4RS)-4anino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-8-chloro-6-fluoro-1-(1R,2S)-2-fluoro-cyclopropyl!-1,4-dihydroloxo-3-quinolinecarboxylic acidas a crude product, in a yield of 84%, which is purified bychromatography over silica gel (mobile phase: methylenechloride/methano/17% strength aqueous ammonia 30:8:1); Melting point:from 192° C. (with decomposition).

EXAMPLE 9 ##STR60##

Under conditions corresponding to those in Example 1,8-chloro-6,7-difluoro-1-(1R,2S)-2-fluoro-cyclopropyl!-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid and (3aRS,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-yl-methyl-aminegive a diastereomer mixture of 8-chloro-6-fluoro-1-(1R,2S)-2-fluorocyclopropyl!-1,4-dihydro-7-(3aRS,4RS)-4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-4-oxo-3-quinolinecarboxylicacid, in a yield of 75%, which can be separated by chromatography oversilica gel, elution first being carried out with the mobile phase systemmethylene chloride/methanol (95:5), and the system then being changed tothe system methylene chloride/methanol/17% strength ammonia (30:8:1).After concentration of the corresponding fractions, the twodiastereomers are obtained in yields of 22% and, respectively, 25% oftheory:

A R_(f) value: 0.28; silica gel, methylene chloride/methanol/17%strength ammonia (30:8:1);

FAB mass spectrum: m/e: 450 (M+H)⁺ !.

B. R_(f) value: 0.19; silica gel, methylene chloride/methanol/17%strength ammonia (30:8:1);

FAB mass spectrum: m/e: 450 (M+H)⁺ !.

EXAMPLE 10 ##STR61## 85 mg (0.76 mmol) of 1,4-diazabicyclo 2.2.2!octaneand 90 mg (0.65 mmol) of(3aSR,4RS)-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine are added to 133mg (0.5 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidin a mixture of 2 ml of acetonitrile and 1 ml of dimethylfolformanide,and the mixture is heated under reflux for 1 hour. It is concentrated at60° C./15 mbar, the residue is treated with about 20 ml of water in anultrasonic bath and the precipitate which has separated out is filteredoff with suction, washed with water and dried at 100° C. in vacuo.

Yield: 108 mg (56% of theory) of 7-(3aSR,4RS)-4-amino-2,3,3a,4,5,6-hexahydro-1H-isoindol-2-yl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,Melting point: 262°-264° C. (with decomposition).

We claim:
 1. Compounds of the formula ##STR62## wherein B represents(CH₂)_(m) --NR³ R⁴ or (CH₂)_(m) --OR⁵, whereinm represents 0 or 1, R³represents hydrogen, alkyl which has 1 to 3 carbon atoms and isoptionally substituted by hydroxyl, acyl having 1 to 3 carbon atoms oralkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part, R⁴represents hydrogen or methyl and R⁵ represents hydrogen or methyl andR⁶ represents hydrogen or methyl.
 2. Compounds according to claim 1,wherein B represents --NR³ R⁴ or --OH.
 3. Compounds according to claim1, wherein B represents --NH₂.
 4. Compounds according to claim 2,wherein R⁶ represents hydrogen.
 5. Compounds according to claim 3,wherein R⁶ represents hydrogen.
 6. Racemic, diastereomerically pure andenantiomerically pure compounds according to claim
 1. 7. Racemic,diastereomerically pure and enantiomerically pure compounds according toclaim
 4. 8. Racemic, diastereomerically pure and enantiomerically purecompounds according to claim
 5. 9. Racemic, diastereomerically pure andenantiomerically pure compounds from the group consistingof2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,4-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,5-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,6-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,7-methyl-2,3,3a,4,5,6-hexahydro-1H-isoindol-4-ylamine,4-methylamino-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-dimethylamino-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-aminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-methylaminomethyl-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-hydroxy-2,3,3a,4,5,6-hexahydro-1H-isoindole,4-hdroxymethyl-2,3,3a,4,5,6-hexahydro-1H-isoindole.